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Cong Yan, PhD

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Dr. Yan’s lab focuses on elucidating molecular and cellular mechanisms by which chronic inflammation induces lung cancer.

Cong Yan, Ph.D.
Professor of Pathology and Laboratory of Medicine
Member of the Center for Immunobiology
Member of IU Simon Cancer Center
Indiana University School of Medicine
Walther Hall C418
980 W. Walnut Street
Indianapolis, Indiana 46202-5188
Phone:317-278-6005
Fax:317-278-7030
E-mail: coyan@iupui.edu

Training:

B.Sc., 1982: Virology, Wuhan University, Wuhan, China
Ph.D., 1987: Biochemistry, City University of New York, New York, NY
Post Doctoral. 1987-1990: The Rockefeller University, Molecular Biology and Biochemistry, New York, NY

Summary of the Research Interests in Dr. Yan’s Laboratory

Lung cancer is one of the biggest public health challenges facing the United States and many other countries. Lung cancer is a difficult disease to detect in its early stages.  In most cases, the tumors are detected at advanced stages and the overall 5 year survival rate is ~15 percent.  It is essential to better understand the events that initiate lung carcinogenesis.

We recently established multiple mouse models supporting a causative relationship between chronic inflammation and lung tumor onset and progression.  Two types of inflammation-induced lung tumor models were established in our lab.  The first group of mouse models uses the lung epithelial-specific CCSP promoter to express “a gene of interest (e.g. Stat3C, Api6, MMP12, dnPPARg)” in a temporal/spatial and inducible manner in lung epithelial cells.  In these mouse models, inflammation was observed in the lung and blood (regional).  The second group of mouse models uses the myeloid-specific c-fms promoter to express “a gene of interest” in a temporal/spatial and inducible manner in myeloid cells.  In these mouse models, inflammation was observed in the bone marrow, blood, spleen, lung and other organs (systemic).  Chronic inflammation in both types of animal models promotes tumor development through nonimmune and immune mechanisms.  The nonimmune mechanism includes uncontrolled epithelial over-growth.  This is initiated by reactivation of the developmental genes that are known to stimulate epithelial growth during lung development. The immune mechanism is the perturbation of hematopoiesis and myelopoiesis, which leads to immune suppression.  The following are areas we are currently working on.

1) Hematopoiesis: Hematopoietic stem cells (HSCs) possess the capacity for self-renewal and the ability to differentiate into all lineages of mature hematopoietic cells.  The production of mature blood cells requires the sequential proliferation and differentiation of HSCs through a successive series of increasingly lineage-restricted intermediate progenitors including common lymphoid progenitors (CLPs), common myeloid progenitors (CMPs), granulocyte-macrophage progenitors (GMPs), and the megakaryocyte-erythroid progenitors (MEPs). Since bone marrow derived myeloid cells participate in inflammation and tissue remodeling in many organs, elucidating the molecular mechanisms governing hematopoiesis during the process of lineage commitment and lineage-specific expansion is critical for understanding inflammation-induced cancer formation.  In systemic inflammation-induced tumor models (driven by the c-fms promoter), HSC development skews toward increase of myeloid progenitor cells in the bone marrow, which leads to expansion of immature myeloid cells in multiple organs.

2) Myelopoisis: A major manifestation in inflammation-induced lung tumor mouse models is the increased level of myeloid-derived suppressor cells (MDSCs) in the lung.

MDSCs are a heterogeneous population of myeloid progenitor cells and immature myeloid cells. In healthy individuals, immature myeloid cells that are generated in the bone marrow quickly differentiate into mature granulocytes, macrophages or dendritic cells (DCs).  Differentiation of immature myeloid cells into mature myeloid cells is blocked in the lung or blood of regional inflammation-induced lung tumor models, or in the lung (as well as other distal organs), blood, spleen and bone marrow of systemic inflammation-induced tumor models. 

3) Immune suppression: MDSCs subvert immune surveillance and prevent the immune system from eliminating newly transformed cells.  Proper proliferation and function of T cells are required for counteracting tumor growth.  In both regional and systemic inflammation-induced lung tumor models, MDSCs inhibit proliferation and function of wild type CD4+ and CD8+ T cells in vitro.  T cell population and function are significantly reduced in lung tumor mouse models. 

4) Biomarker identification: Since lung epithelial cell-initiated regional inflammation and myeloid cell-initiated systemic inflammation induce lung tumorigenesis, these inflammatory animal models are ideal and valuable systems for identification and verification of lung cancer biomarkers.  During the pathogenic process of chronic inflammation and lung tumorigenesis in these animal models, a common feature is Stat3 over-activation in lung epithelial cells, suggesting that Stat3 activation plays a critical role in inflammation-induced lung tumorigenesis.  When a constitutive active form of Stat3C is over-expressed in alveolar type II epithelial cells, it directly induces pulmonary inflammation and adenocarcinoma in the lung.  Affymetrix GeneChip microarray analysis reveals around 800 Stat3 downstream genes in the lung.  When tested in animals and humans, some of these genes show a great potential to be used as biomarkers for lung cancer prediction. 

5) Bone marrow mesenchymal stem cells to lung epithelial cell transdifferentiation.  The lung has the largest epithelial surface area of the body in order to facilitate air exchange. Alveolar type II (AT II) epithelial cells synthesize and secrete pulmonary surfactant that is critical to prevent alveoli from collapse during respiratory cycles. AT II epithelial cells also participate in pulmonary inflammation and injury repair. In the lung, AT II epithelial cells are the local progenitor cells for the alveoli and undergo significant phenotypic changes to terminally differentiate into AT I cells. Since the lung is constantly exposed to a range of insults from the surrounding environment, maintenance of lung function requires both host defense and epithelial cell damage repair. AT II epithelial cells also serve as local tumor progenitor cells. Bone marrow mesenchymal stem cells (BMSCs) have multiple potentials to convert into residential cells in multiple organs. They can be used for regenerative medicine, tissue repair and gene therapy.  We demonstrate that BMSCs are able to convert into AT II epithelial cells as a result of pulmonary remodeling and injury (emphysema and hypercellularity) under the inflammatory condition.

6) Prenatal and neonatal lung development:  The lung originates as a diverticulum from the foregut. In early lung development, the primitive lung is a small epithelial tubule surrounded by mesenchymal cells. Through the interaction with mesenchymal cells, lung epithelium undergoes multiplication of branches and subsequently forms airways and alveoli, forming proximal and distal structures. This process is dependent and influenced by many signaling molecules through paracrine/autocrine mechanisms. We show that reactivation of lung developmental genes contributes to respiratory epithelial cell cancerous transformation under chronic inflammation.

 

Publications:

Cong Yan (co-corresponding author), Xuemei Lian, Yuan Li, Amanda White, Yulin Qin, Huimin Li, Ying Dai, David A. Hume, and Hong Du (co-corresponding author): Macrophage-specific Over-expression of Human Lysosomal Acid Lipase Corrects Inflammation and Pathogenic Phenotypes in lal-/- Mice (2006). The American Journal of Pathology, 169(3):916-926. PMID: 16936266.

Yuan Li, Yulin Qin, Huimin Li, Renlian Wu, Cong Yan (co-corresponding author) and Hong Du: Lysosomal Acid Lipase Overexpression Disrupts Lamellar Body Genesis and Alveolar Structure in the Lung (2007). International Journal of Experimental Pathology, 88(6):427-36. PMID: 18039279.

Cong Yan (co-corresponding author), Xuemei Lian, Ying Dai, Amanda White, Yulin Qin, Xi Wang, Peng Qu and Hong Du: Gene Delivery by hSP-B Promoter in Lung Alveolar Type II Epithelial Cells in LAL Knock-out Mice through Bone Marrow Mesenchymal Stem Cells (2007). Gene Therapy, 14: 1461-1470. PMID: 17700706.

Yuan Li, Hong Du, Yulin Qin, Jennifer Roberts, Oscar W. Cummings and Cong Yan (corresponding author): Activation of the Stat3 Pathway in Alveolar Epithelial Cells Induces Inflammation and Adenocarcinomas in Mouse Lung (2007). Cancer Research, 67(18):8494-8503. PMID: 17875688.

Peng Qu, Jennifer Roberts, Yuan Li, Marjorie Albrecht, Oscar W. Cummings,John N. Eble, Hong Du and Cong Yan (corresponding author): Stat3 Downstream Genes Serve as Biomarkers in Human Lung Carcinomas and Chronic Obstructive Pulmonary Disease (2009). Lung Cancer, 63(3):341-7. PMID: 18614255.

Peng Qu, Hong Du, Yuan Li and Cong Yan (co-corresponding author). Myeloid-Specific Expression of Api6/AIM/Sp{alpha} Induces Systemic Inflammation and Adenocarcinoma in the Lung (2009). The Journal of Immunology 182, 1648-1659. PMID: 19155514.

Peng Qu, Hong Du, Yuan Li, David S. Wilkes, and Cong Yan (co-corresponding author): Critical Roles of Lysosomal Acid Lipase in T Cell Development and Function (2009). The American Journal of Pathology, 174:944-956. PMID: 19179613.

Peng Qu, Hong Du, Xi Wang and Cong Yan (corresponding author): Matrix-metalloproteinase 12 Overexpression in Lung Epithelial Cells Plays a Key Role in Emphysema to Lung Bronchioalveolar Adenocarcinoma Transition (2009). Cancer Research, 69(18):7252-61. PMID: 19706765.

Peng Qu, William C. Shelley, Mervin C. Yoder, Lingyan Wu, Hong Du and Cong Yan (corresponding author): Critical Roles of Lysosomal Acid Lipase in Myelopoiesis (2010). The American Journal of Pathology, 176:2394-2404. PMID: 20348241.

Lingyan Wu, Guixue Wang, Peng Qu, Cong Yan (co-corresponding author), and Hong Du: Overexpression of Dominant Negative Peroxisome Proliferator-Activated Receptor-g in Alveolar Type II Epithelial Cells Causes Inflammation and T Cell Suppression in the Lung (2011). The American Journal of Pathology, 178:2191-2204. 

Peng Qu, Cong Yan (co-corresponding author), and Hong Du: Matrix Metalloproteinase 12 Over-expression in Myeloid Lineage Cells Plays a Key Role in Modulating Myelopoiesis, Immune Suppression and Lung Tumorigenesis (2011). Blood, 117(17):4476-4489.

Yuan Li, Peng Qu, Lingyan Wu, Beilin Li, Hong Du and Cong Yan (co-corresponding author): Api6/AIM/Spa/CD5L Overexpression in Alveolar Type II Epithelial Cells Induces Spontaneous Lung Adenocarcinoma (2011). Cancer Research, 71(16):5488-99, PMID: 21697282.

Lingyan Wu, Hong Du, Yuan Li, Peng Qu and Cong Yan (corresponding author): Signal Transducers and Activators of the Transcription 3 Promotes Myeloid-derived Suppressor Cell Expansion and Immune Suppression during Lung Tumorigenesis (2011). The American Journal of Pathology, 179(4):2131-41. PMID: 21864492.

Peng Qu, Cong Yan (corresponding author), Janice S. Blum, Reuben Kapur and Hong Du: Myeloid-Specific Expression of Human Lysosomal Acid Lipase Corrects Malformation and Malfunction of Myeloid-derived Suppressive Cells in lal-/- Mice (2011). The Journal of Immunology, 187(7):3854-66. PMID: 21900179.

Lingyan Wu, Cong Yan (co-corresponding author), Magdalena Czader, Oded Foreman, Janice S. Blum, Reuben Kapur and Hong Du: Inhibition of Peroxisome Proliferator-Activated Receptor-g in Myeloid Lineage Cells Induces Systemic Inflammation, Immunosuppression and Tumorigenesis. Blood, In press.

Dept. of Pathology & Laboratory Medicine Administration Office | Van Nuys Medical Science Building | 635 Barnhill Drive, room A-128 | Indianapolis, IN 46202 Indiana University Health Pathology Laboratory: 350 W. 11th Street, Indianapolis, Indiana 46202